Background/Purpose: Studies in murine models for SLE have shown that CTLA4Ig can ameliorate murine lupus nephritis.  Moreover, the combination of CTLA4Ig plus intravenous cyclophosphamide (IVC) acts synergistically in mice to reverse lupus nephritis.  The purpose of this study (the ACCESS Trial) was to determine whether these observations in mice could be translated into an effective treatment for lupus nephritis in people.

Methods: Subjects with biopsy-proven class III or IV lupus nephritis (with or without class V) and urine protein:creatinine ratio (UPCR) >1 were enrolled in the trial.  All subjects received low-dose IVC (500 mg q 2 wks x 6) followed by azathioprine (2 mg/kg/d up to a maximum of 200 mg/dose), per the Euro-Lupus nephritis (ELN) regimen.  Subjects were randomized 1:1 to receive either saline (n=68) or abatacept (ABA) (n=66) intravenously at weeks 0, 2, 4, and then every four weeks.  ABA was dosed based on weight: <60 kg, 500 mg; 60-100 kg, 750 mg; >100 kg, 1 gm.  In addition, subjects received oral prednisone beginning at 60 mg/d and tapered to 10 mg/d within 12 weeks.  The primary outcome measure was complete response (CR) at 24 weeks, defined as: (i) UPCR <0.5; (ii) serum creatinine normal or, if abnormal, within 25% of baseline; and (iii) adherence to the steroid regimen.  Partial response required a >50% improvement in UPCR and otherwise mirrored the CR criteria.

Results: A racially and ethnically diverse population of North American subjects was enrolled (39% African American and 40% Hispanic/Mestizo).  The groups were well matched for baseline characteristics, including race, ethnicity, severity of nephritis, and biopsy class.  At 24 weeks, the CR rate in the ABA group was 22/66 (33%) compared to 21/68 (31%) in the control group (p=0.85).  Total response (CR+PR) was 59% in both groups (39/66 vs 40/68).  Among African American subjects, 33% (9/27) of subjects in the ABA group achieved CR, compared to 16% (4/25) in the control group (p=0.20).  Twice as many subjects in the ABA group experienced disappearance of anti-dsDNA Ab (24% vs 11%), but the difference was not statistically significant (p=0.22).  Patient global assessment improved by 74% in the ABA group compared to 38% in the control group (p=0.051).  There was no difference between the groups at week 24 in mean UPCR, anti-dsDNA and complement levels, BILAG score, SF-36 (physical and mental), frequency of serious adverse events (SAEs), or withdrawals (total or lupus-related).   The rate of infectious SAEs was 0.3/yr in the ABA group compared to 0.2/yr in the control group (NS). 

Conclusion: The ACCESS trial did not achieve its primary goal of demonstrating a benefit for ABA plus ELN compared to ELN alone at 24 weeks.  However, it achieved an important secondary objective by providing the first systematic examination of the ELN regimen in a racially and ethnically diverse North American population.  The response rate of >30% CR within 24 weeks in the ELN control group is higher than has been reported in prior lupus nephritis trials (including studies of mycophenolate mofetil and high-dose IVC), suggesting that the ELN regimen may have broad applicability.  Subjects in the ACCESS trial are still undergoing blinded evaluation to examine outcome at later time points.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-of-lupus-nephritis-with-abatacept-plus-low-dose-pulse-cyclophosphamide-followed-by-azathioprine-the-euro-lupus-regimen-twenty-four-week-data-from-a-double-blind-controlled-trial/